N,n&#39;-bis(2-aryl-2-(hydroxy or oxo)-ethyl)-bridged-bis-carboxamides

ABSTRACT

CONDENSATION OF AN AMIDE OF THE FORMULA   AR-CO-CH2-NH2   AND A DIACID DIHALIDE OF THE FORMULA   Z-CO-X-CO-Z   PROVIDES N,N&#39;&#39; - BIS(2-ARYL-2-OXOETHYL)-BRIDGED-BISCARBOXAMIDES OF THE FORMULA   AR-CO-CH2-NH-CO-X-CO-NH-CH2-CO-AR   REDUCTION OF WHICH PROVIDES N,N&#39;&#39;-BIS(2-ARYL-2-HYDROXYETHYL)-BRIDGED-BISCARBOXAMIDES OF THE FORMULA   (AR-CH(-OH)-CH2-NH-CO)2-X   AND N,N&#39;&#39;-BRIDGED-BIS(2-ARYL-2-HYDROXYETHYLAMINES) OF THE FORMULA   (AR-CH(-OH)-CH2-NH-CH2)2-X   THE LATTER COMPOUNDS ARE ALSO PREPARED BY CONDENSATION OF AN EPOXIDE OF THE FORMULA   AR-CH&lt;(-O-CH2-)   WITH A DIAMINE OF THE FORMULA   NI2-CH2-X-CH2-NH2   THE PRODUCTS HAVE ANTIBACTERIAL ACTIVITY IN VITRO AND ARE USEFUL AS ANTIBACTERIAL AGENTS.

United States Patent Ofice Patented Nov. 27, 1973 3,775,477N,N'-BIS[2-ARYL-2-(HYDROXY R 0X0)-ETHYL]- BRlDGED-BIS-CARBOXAMIDES GuyD. Diana, Stephentown, N.Y., assignor to Sterling Drug Inc., New York,N.Y. No Drawing. Filed Mar. 10, 1971, Ser. No. 123,095 Int. Cl. C07c103/38, 103/42 US. Cl. 260-558 A 19 Claims ABSTRACT OF THE DISCLOSURECondensation of an amine of the formula 0 Ar-ii-CIfi-NHZ and a diaciddihalide of the formula provides N,Nbis[2-aryl-2-oxoethyl]-bridged-biscarboxamides of the formulaethyl]-bridged-biscarboxamides of the formula andN,N'-bridged-bis[2-aryI-Z-hydroxyethylamines] of the 0 formula 3 Thelatter compounds are also prepared by condensation of an epoxide of theformula O 1 Ar-CH H2 with a diamine of the formula NH C-H -X-CH NH Theproducts have antibacterial activity in vitro and are useful asantibacterial agents.

This invention relates to compositions of matter classified in the artof organic chemistry as N,N'-bis[2-aryl-2- hydroxy oroxo-ethyl]-bridged-biscarboxamides and to processes for preparing them.

In its composition of matter aspect my invention provides N,N bis[2(Ar)-2-(Y)-2-(Y')-ethyl]-(X)-biscarboxamide of the formula the adjacentcarbon atoms at different carbon atoms; Y, when taken alone, ishydrogen; Y, when taken alone, is hydroxyl; and Y, when taken togetherwith Y, is carbonyl oxygen.

The compounds of Formula I have antibacterial activity in vitro and areuseful as antibacterial agents. The compounds of Formula I wherein Y andY taken together are carbonyl oxygen, namely N,N-bis[2-(Ar)-2-oxoethyl]-(X)-biscarboxamides, are also useful as intermediates for thepreparation of N,N-[methylene-(X)-methylene]-bis-[2-(Ar)-2.-hydroxyethylamines of the formula H? OH Ar-oH-0Hr-NHCH,-x-cH,-NH-cm-dH-Ar (Formula II) wherein Ar and X have the samemeanings ascribed thereto above in Formula I. The compounds of FormulaII and acid-addition salts thereof also have antibacterial activity invitro and are useful as antibacterial agents.

In one of its process aspects my invention provides the process forpreparing N,N'-bis[2-(Ar)-2-oxoethyl]- (X)-bis-carboxamide of Formula I,wherein Y and Y' taken together are carbonyl oxygen, which comprisescondensing an amine of the formula (Formula III) 0 Z( i-X -Z (FormulaIV) wherein Ar of Formula IE and X of Formula IV have the same meaningsascribed thereto above in Formula I and Z is chloro or bromo.

In a second process aspect my invention provides the process forpreparing N,N-bis[2-(Ar)-2-hydroxyethyl]- (X)-biscarboxamide of FormulaI, wherein Y is hydrogen and Y is hydroxyl, which comprises reducingN,N'- bis[2-(Ar)-2-oxoethyl]-(X)-biscarboxamide of Formula I, wherein Yand Y taken together are carbonyl oxygen, with sodium borohydride.

In a third process aspect my invention provides the process forpreparing N,N-[methylene-(X)-methylene]- bis[2-(Ar) 2 hydroxyethylamine]of Formula II which comprises reducing N,N-bis[2-(Ar)-2-oxoethyl]-(X)-biscarboxamide of Formula I, wherein Y and Y taken together are carbonyloxygen, with diborane, lithium aluminum hydride, trialkylaluminum ordialkylaluminum hydride, wherein alkyl of trialkylaluminum anddialkylaluminum is ethyl, propyl, isopropyl, butyl, isobutyl orseebutyl.

An alternative process for preparing N,N'-[methylene-(X)-methylene]-bis[2-(Ar) 2 hydroxyethylamine] of Formula II comprisescondensing an epoxide of the forwith a diamine of the formula (Formulawherein Ar of Formula V and X of Formula VI have the same meaningsascribed thereto above in Formula I. When Ar is phenyl substituted bynon-tertiary alkyl of one to four carbon atoms, non-tertiary alkyl ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl.

(Formula V When Ar is phenyl substituted by non-tertiary alkoxy of oneto four carbon atoms, non-tertiary alkoxy is methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy or sec-butoxy.

When Ar is phenyl substituted by halo, halo is fluoro, chloro, bromo oriodo.

When X is alkylene of two to ten carbon atoms with bonds to the adjacentcarbon atoms at different carbon atoms, it can be unbranched orbranched. If unbranched, X is 1,2-ethylene, 1,3-propylene, 1,4-butylene,1,5-pentylene, 1,6-hexylene, 1,4-heptylene, 1,8-octylene, 1,9-nonyleneor 1,10-decylene. If branched, X is, for example, 2-methyl-1,4-butylene. Since X and the attached methylenes are integral inthe compounds of Formula II, they are named integrally. Thus, theillustrated alkylenes become, respectively, 1,4-butylene, 1,5-pcntylene,1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene,1,11-undecylene, 1,12-dodecylene and 3-methyl-1,6- hexylene.

The manner and process of making and using the invention and the bestmode of carrying it out will now be described so as to enable any personskilled in the art to which it pertains to make and use it.

The preferred method for carrying out the process of condensing an amineof Formula III with a diacid dihalide of Formula IV is the use of anacid addition salt of the amine of Formula III, for example, thehydrochloride or the hydrobromide, an acid acceptor, for example,triethylamine or pyridine, and a solvent inert under the reactionconditions, for example, acetonitrile, benzene, chloroform,N,N-dimethylformamide or tetrahydrofuran at a temperature in the rangeof to 100 C. The hydrochloride is the preferred amine salt,triethylamine is the preferred acid acceptor, chloroform is thepreferred solvent and room temperature is the preferred temperature.

The preferred method for carrying out the process of reducingN,N-bis[2-(Ar)-2-oxoethyl] (X) biscarboxamide of Formula I, wherein Yand Y taken together are carbonyl oxygen, with sodium borohydride is theuse of methanol as a solvent at a temperature in the range of 0 to 70 C.A cosolvent, for example, dioxane or tetrahydrofuran, can also be used.

The preferred method for carrying out the process of reducingN,N'-bis[2-(Ar)-2-oxoethyl] (X) biscarboxamide of Formula I, wherein Yand Y taken together are carbonyl oxygen, with diborane, lithiumaluminum hydride, trialkylaluminum or dialkylaluminum hydride is the useof a solvent inert under the reaction conditions, for example, benzene,1,2-dimethoxyethane, heptane, dioxane or tetrahydrofuran at atemperature in the range of 0-120 C. Tetrahydrofuran is the preferredsolvent and the reflux temperature of the tetrahydrofuran solution ofthe reactants is the preferred temperature. Examples of trialkylaluminumand dialkylaluminum hydride as the reducing agent in the present processinclude triethylaluminum, triisopropylaluminum, triisobutylaluminum,diethylaluminum hydride, diisopropylaluminum hydride anddiisobutylaluminum hydride.

The preferred method for carrying out the process of condensing anepoxide of Formula V with a diamine of Formula V1 is the use of asolvent inert under the reaction conditions, for example, acetonitrile,benzene, chloroform, N,N-dimethylformamide, ethanol, methanol ortetrahydrofuran at a temperature in the range of 0 to 100 C.Acetonitrile is the preferred solvent and the reflux temperature of theacetonitrile solution of the reactants is the preferred temperature.

Formation of acid-addition salts of the compounds of Formula H isaccomplished by standard methods with any pharmaceutically acceptableinorganic (mineral) or organic acid. If inorganic, the acid can be, forexample, hdrochloric acid, hydrobromic acid, nitric acid, hosphoric acidor sulfamic acid. If organic, the acid can be, for example, acetic acid,glycolic acid, lactic acid, quinic acid,

hydrocinnamic acid, succinic acid, tartaric acid, citric acid,methanesulfonic acid or benzenesulfonic acid.

That the acid be pharmaceutically acceptable means that the beneficialproperties inherent in the free base not be vitiated by side effectsascribable to the anions.

Although pharmaceutically acceptable salts are preferred, allacid-addition salts are within the scope of the invention. Apharmaceutically unacceptable salt may be useful, for example, forpurposes of identification or purification or in preparing apharmaceutically acceptable salt by ion-exchange procedures.

The intermediate amines of Formula III are a known class of compounds,which may be prepared, for example, by brominating the correspondingacetophenone, treating the resulting a-bromoacetophenone withhexamethylenetetramine and treating the resulting product with ethanolichydrochloric acid, thus producing the hydrochloride salt.

The intermediate diacid dihalides of Formula IV are also a known classof compounds, which may be prepared, for example, by treating thecorresponding diacid with thionyl chloride or thionyl bromide.

The intermediate epoxides of Formula V are a known class of compounds.Their preparation is accomplished by epoxidation of the correspondingstyrenes by any of several well-known methods, for example, by the useof peracetic acid buffered with sodium acetate. The styrenes are knowncompounds, some of which are commercially available.

The intermediate diamines of Formula VI are also a known class ofcompounds, some of which are commercially available. Preparation ofthose which are not commercially available is accomplished by well-knownmethods, for example, by reductive amination of the correspondingdiketone or dialdehyde, amination of the corresponding dihalide ordialcohol p-toluenesulfonate diester or reduction of the correspondingdinitrile, dioxime, diamide, diazide or other di-higher-oxidation-statenitrogen compound. Unsymmetrical diamines can be prepared fromunsymmetrical starting materials.

The compounds of Formula I and acid-addition salts thereof and thecompounds of Formula II are purified by recrystallization. Theirstructures follow from their route of synthesis and are corroborated byinfrared spectral analysis and by the correspondence of calculated andfound values of elemental analysis of representative samp es.

As stated above the compounds of Formula I and acidaddition saltsthereof and the compounds of Formula H have antibacterial activity invitro, which was determined by a standard serial dilution test. In thistest the concentration of compound arresting the growth of themicroorganism is the bacteriostatic concentration and is expressed inparts per million (ppm). The concentration of compound preventing growthof the microorganism after further incubation is the bactericidalconcentration and is also expressed in parts per million.

The compounds of Formula I and acid-addition salts thereof and thecompounds of Formula II are useful as antibacterial agents and areespecially useful for disinfecting and sanitizing living and non-livingsurfaces by conventional swabbing, padding, spraying, immersing, rinsingand the like techniques. Depending on the particular purpose involved,the compounds are used in aqueous solution, in aqueous detergentsolutions or in solutions in organic solvents.

The following examples illustrate specific embodiments of my inventionwithout limiting the latter thereto.

EXAMPLE 1 Adipoyl chloride (9.93 g.) was added dropwise with stirring toa filtered mixture of a-amino-p-bromoacetophenone hydrochloride (26.7g.), triethylamine (21.9 g.) and chloroform (500 ml.) and stirring wascontinued (for 1 hr.) at room temperature. Recrystallization of theresuiting solid (19 g.) from N,N-dimethylformamide gave N,N'-bis[2-(pbromophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide (I: Ar=p-BrC 4 X=(CH Y+Y'= (12.3 g., M.P. 254.0256.0 C.).

Table I shows the results of the antibacterial testing in vitro ofN,N-bis[2-(p-bromophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide.

N,N-bis[2-(p-bromophenyl) 2 0xoethyl]-1,4-butylenebiscarboxarnide (16.7g.) was added in small portions with stirring and with the reactiontemperature maintained at 0 C. to a solution of diborane (1 M, 248 ml.)in tetrahydrofuran. The solution was heated under reflux and undernitrogen (for 1 /2 hr.). Hydrochloric acid (6 M, 35 ml.) was added, theresulting solid was separated by filtration and the filtrate wasstripped of tetrahydrofuran. Water (100 ml.) and sodium hydroxide (35%,20 ml.) were added to the combined residue and solid and the mixture wasstirred (for 30 min.). Since the resulting solid appeared to be amixture of hydrochloride salt and free base, it was suspended inmethanol and treated with hydrochloric acid. A solution of the resultingsolid in water (1 l.) was filtered and the filtrate was basified withaqueous ammonia. Recrystallization of the resulting solid (13.7 g.) fromethyl acetate gave N,N'- (1,6-hexylene)-bis[2- (p bromophenyl) 2hydroxyethylamine] (II: Ar=p-BrC H X=(CH (10.5 g., M.P. 1453-1490" 0.

Table II shows the results of the antibacterial testing in vitro ofN,N'-(1,6-hexylene)-bis[2-(p-bromophenyl)- 2-hydroxyethylamine] (A) Asolution of styrene oxide (22.0 g.), hexamethylenediamine (11.6 g.) andacetonitrile (100 ml.) was heated under reflux overnight, then cooled.Two recrystallizations of the resulting solid from ethanol gave N,N'-1,6 hexylene)-bis[Z-phenyl-2-hydroxyethylamine] (II: Ar=C H X=(CH (3.9g., M.P. 158159.4 C.).

Table III shows the results of the antibacterial testing in vitro ofN,N'-(1,6-hexylene)-bis[2-phenyl-2-hydroxyethylamine] TABLE IIIConcentration (p.p.m.)

Bacterio- Bacteri- Microorganism static cldal Staphylococcus aureus 100100 Eberthella typhi 100 100 Clostridium welchii 100 Pseudomonasueruginosu 75 100 Treatment ofN,N'-(1,6-hexylene)-bis[2-phenyl-2-hydroxyethylamine] with hydrochloricacid, hydrobromic acid, nitric acid, phosphoric acid, sulfamic acid,acetic acid, glycolic acid, lactic acid, quinic acid, hydrocinnamicacid, succinic acid, tartaric acid, citric acid, methanesulfonic acidand benzenesulfonic acid affords, respectively, the followingacid-addition salts:

N,N-( 1,6-hexylene) -bis [2-phenyl-Z-hydroxyethylamine] dihydrochloride,

N,N'- 1,6-hexylene) -bis [2-phenyl-Z-hydroxyethylamine] dihydrobromide,

N,N'-( 1,6-hexylene) -bis 2-phenyl-2-hydroxyethylamine] dinitrate,

N,N'-( 1,6-hexylene) -bis [2-phenyl-2hydroxyethylamine] diphosphate,

N,N'-( 1,6-hexy1ene) -bis[2-phenyl-2-hydroxyethylamine] disulfamate,

N,N'- 1,6-hexylene) -bis [Z-phenyl-Z-hydroxyethylamine] diacetate,

N,N'- l ,6-hexylene) -bis 2-phenyl-2-hydroxyethylamine] diglycolate,

N,N'-( 1,6-hexylene) -bis [2-phenyl-2-hydroxyethylamine] dilactate,

N,N'- 1,6-hexylene) -bis 2-phenyl-2-hydroxyethylamine] diquinate,

N,N'- 1,6-hexylene) -bis 2-phenyl-Z-hydroxyethylamine] dihydrocinnamate,

N,N-( 1,6-hexylene) -bis[2-phenyl-Z-hydroxyethylamine] succinate,

N,N'- 1,6-hexylene) -bis 2-phenyl-Z-hydroxyethylamine] tartrate,

N,N'-( 1,6-hexylene) -bis [2-phenyl-2-hydroxyethylamine1 dicitrate,

N,N'-( 1,6-hexylene) -bis[2-phenyl'2-hydroxyethylarnine]dimethanesulfon-ate and N,N'-( 1,6-hexylene) -bis[2-phenyl-2-hydroxyethylamine] dibenzenesulfonate.

(B) Condensation of a-aminoacetophenone hydrobromide and adipoyl bromideaffords N,N'-bis[2-phenyl- 2 oxoethyl] 1,4-butylenebiscarboxamide (I:Ar=C H X: 4,

Reduction of N,N'-bis [2-phenyl-2-oxoethyl] -l,4-butylenebiscarboxamidewith diborane also affords N,N (1,6- hexylene) -bis[2-pheny1-2-hydroxyethylamine] EXAMPLE 3 Condensation ofu-amino-o-methylacetophenone hydrobromide and adipoyl bromide atfordsN,N-bis[2-(omethylphenyl) 2-oxoethyl]-1,4butylenebiscarboxamide I:Ar=o-CH C H X= (CH Y+Y =0).

Reduction of N,N'-bis[2- (o-methylphenyl)-2-oxoethy1]-1,4-butylenebiscarboxamide with diborane affords N,N'-(1,6-hexylene)-bis[Z-(o-methylphenyl) 2-hydroxyethylamine] (II: Ar=o-CHC H X= (CH EXAMPLE 4 Condensation of a-amino-p-isopropylacetophenonehydrochloride and adipoyl chloride aifords N,N'-bis[2-(pisopropylphenyl) 2 oxoethyl]-1,4-butylenebicarboxamide (II Ar=p-(CH CHCH X=(CH2)4,

Reduction of N,N' bis[2-(p-isopropylphenyl)-2-oxoethyl] 1,4butylenebiscarboxamide with diborane af- .fords N,N' (1,6hexylene)-bis[2-(p-isopropylphenyl)- 2 hydroxyethylamine] (II: Ar=p-(CHCHC H 2)4)- 7 EXAMPLE 5 In a manner similar to that of Example 1,condensation of a-amino-p-methoxyacetophenone hydrochloride (66.7 g.)and adipoyl chloride (30.4 g.) and two recrystallizations of part (11.7g.) of the product from N,N-dimethylformamide gaveN,N'-bis[2-(p-methoxyphenyl) 2 oxoethyl] 1,4-butylenebiscarboxamideReduction of N,N-bis[2-(p-methoxyphenyl) 2 oxoethyl] 1,4butylenebiscarboxamide with diborane affords N,N' 1,6 hexylene) bis[2(p-methoxyphenyl)- 2-hydroxyethylamine] (II: Ar=p-CH OC H 7 EXAMPLE 6Condensation of a-amino-p-(sec-butoxy)acetophenone hydrochloride andadipoyl chloride affords N,N-bis[2-(p- (sec-butoxy)phenyl) 2oxoethyl]-1,4-butylenebiscarboxamide (I: Ar=p-CH CH (CH )CHOC HReduction ofN,N-bis[2-(p-(sec-butoxy)phenyl)-2-oxoethyl]-1,4-butylenebiscarboxamidewith diborane affords N,N' (1,6-hexylene) bis[2 (p-sec-butoxy)phenyl)-2-hydroxyethylamine] (I-I: Ar=p-CH CH (CH )CHOC H X: (CH

EXAMPLE 7 Condensation of a-amino-p-fluoroacetophenone hydrochloride andadipoyl chloride affords N,N'-bis[2-(pfiuorophenyl) 2 oxoethyl] 1,4butylenebiscarboxamide (I: Ar==p-FC H X=(CH Y+Y'=0).

Reduction of N,N-bis[2-(p-fluorophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide with diborane affords N,N'-(1,6-hexylene)-bis[2-(p-fluorophenyl) 2 hydroxyethylamine] (II: Ar=p-FCH X: (CH

EXAMPLE 8 (A) In a manner similar to that of Example 1, condensation ofa-amino-m-chloroacetophenone hydrochloride (40 g.) and adipoyl chloride(17.75 g.) and recrystallization of the resulting product fromN,N-dimethylformamide gave N,N' bis[2 (m chlorophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide (I: Ar=m-ClC H X=(CH Y+Y'=0), (30 g., M.P.198.6-200.2 C.).

A solution of lithium aluminum hydride (3.58 g.) in tetrahydrofuran (500ml.) was heated under reflux with stirring overnight in a Soxhletextraction apparatus containing N,N' bis[2 (m chlorophenyl)-2-oxoethyl]-1,4 butylenebiscarboxamide (17.3 g.) in the extraction thimble. Asolution of water (8 ml.) and tetrahydrofuran (8 ml.) was added.Separation of the solid by filtration and chilling the filtrate gave asolid (7 g.), which was combined with material from another run andrecrystallized from N,N-dimethylformamide, affording N,N'-(1,6-hexylene)bis [2 (m-chlorophenyl)-2-hydroxyethylamine] (II: Ar=m-ClC H X=(CH (10.9g., M.P. 141.8- 146.6' C.).

(B) Reduction of N,N' bis[2 (m chlorophenyl)- 2-oxoethyl] 1,4butylenebiscarboxamide with triethylaluminum also affords N,N'(1,6-hexylene)-bis[2-(mchlorophenyl) -2-hydroxyethylamine] (C) Reductionof N,N' bis[2 (m-chlorophenyD-Z- oxoethyl] 1,4 butylenebiscarboxamidewith diisopropylaluminum hydride also affords N,N'-(1,6-hexylene)- bis[Z-(m-chlorophenyl -2-hydroxyethylamine] EXAMPLE 9 In a manner similarto that of Example 1, condensation of u-amino p chloroacetophenonehydrochloride (76.4 g.) and adipoyl chloride (32.2 g.) andrecrystallization of part (20 g.) of the product (70.3 g.) fromN,N-dimethylformamide gave N,N'-bis[2-(p-chlorophenyl) 2 oxoethyl] 1,4butylenebiscarboxamide (I: Ar=p-ClC H X=(CH2)4 Y+Y'=0) (16 g., M.P.260.0-264.0 0.

In a manner similar to that of Example 1, reduction ofN,N-bis[2-(p-chlorophenyl) 2 oxoethyl] 1,4 butyleuebis carboxamide (31g.) with diborane (1 M in tetrahydrofuran, 562 ml.) andrecrystallization of the resulting product first from ethanol and thentwice from methanol gave N,N-(1,6-hexylene)-bis[2- (p-chlorophenyl 2hydroxyethylamine] (II: Ar=p-ClC H X=(CH (7.6 g., M.P. 156.0159.4 C.).

EXAMPLE 10 Condensation of a-amino-p-iodoacetophenone hydrochloride andadipoyl chloride affords N,N'-bis[2-(p- 8 iodophenyl)-Z-oxoethyl] 1,4butylenebiscarboxamide (I: AI=P-IC6H4, X: (CI-12).,

Reduction of N,N'-bis[2-(p iodophenyl) 2oxoethyl]-1,4-butylenebiscarboxamide with diborane affordsN,N-(1,6-hexylene) bis[2 (p iodophenyl) 2 hydroxyethylamine] (II:Ar=p-IC H X: (CH

EXAMPLE 11 In a manner similar to that of Example 1, condensation ofot-amino 3,4 dichloroacetophenone hydrochloride (15.46 g.) and adipoylchloride (5.63 g.) and recrystallization of the resulting product (9.7g.) from methanol gave N,N-bis[2-(3,4-dichlorophenyl)-2 oxoethyl] 1,4-butylenebiscarboxamide (I: Ar=3,4-Cl C H Y+Y'=0) (8.0 g., M.P.188.0-198.0 0.).

Reduction ofN,N-bis[2-(3,4-dichlorophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamidewith diborane affords N,N'-(1,6 hexylene) bis[2 (3,4 dichlorophenyl)-2-hydroxyethylamine] (II: Ar=3,4-Cl C I-I X=(CH EXAMPLE 12 EXAMPLE 13Condensation of u-amino-3,5-dichloro 2 methoxyacetophenone hydrochlorideand adipoyl chloride affords N,N'-bis[2-(3,5 dichloro 2 methoxyphenyl) 2oxoethyl] 1,4 butylenebiscarboxamide (I: Ar=3,5-Cl -2- CH3OC6HZ,X=(CHZ)4,

Reduction of N,N'-bis[2-( 3,5 dichloro 2 methoxyphenyl)-2-oxoethyl] 1,4butylenebiscarboxamide with diborane affords N,N'-1,6-hexylene)-bis[2-(3,5-dichloro- 2-methoxyphenyl)-2 hydroxyethylamine](II: Ar=3,5- Cla-2-CH30c H2, X: (CH2)4).

EXAMPLE l4 Condensation of a-amino m (trifluorornethyDacetophenonehydrochloride and adipoyl chloride affords N,N-bis[Z-(m-(trifluoromethyl)phenyl) 2 oxoethyl] 1,4-butylenebiscarboxamide (I: Ar=m-CF C H Reduction of N,N'-bis[2-(m-(trifiuoromethyl)phenyl)- 2-oxoethyl] 1,4 butylenebiscarboxamide withdiborane affords N,N'-(1,6-hexylene)-bis[2-(m (trifiuoromethyl) phenyl)2 hydroxyethylamine] (II: Ar=m-CF C H X: 2)4)' EXAMPLE 15 Condensationof u-amino p (dimethylamino)acetophenone hydrochloride and adipoylchloride affords N,N'- bis[2-(p-(dimethylamino)pheny1) 2 oxoethyl] 1,4-butylenebiscarboxamide (I: Ar=p-(CH NC H Reduction of N,N-bis [2- (p-(dimethylamino) phenyl 2-oxoethyl] 1,4 butylenebiscarboxamide withdiborane affords N,N-( l,6-hexylene)-bis[2 (p (dimethylamino)phenyl)-2-hydroxyethylamine] (II: Ar=p-(CH NC H 2)4)- 9 EXAMPLE 16Condensation of a-amino p acetamidoacetophenone hydrochloride andadipoyl chloride affords N,N'-bis[2- (p-acetamidophenyl) 2 oxoethyl] 1,4butylenebiscarboxamide (I: Ar=p-CH CONHC H X= (CH h, Y+Y'=0).

Reduction of N,N-bis[2-(p-acetamidophenyl) 2oxoethyl]-1,4-butylenebiscarboxamide with diborane affordsN,N'-(1,6-hexylene) bis[2 (p acetamidophenyl) 2- hydroxyethylamine] (II:Ar=p-CH CNHC H EXAMPLE 17 In a manner similar to that of Example 1,condensation of a-amino-m-nitroacetophenone hydrochloride (27 g.) andadipoyl chloride (11.4 g.) and two recrystallizations of the resultingproduct (18.1 g.) from nitromethane gaveN,N'-bis[2-(m-nitrophenyl)-2-oxoethyl]-1,4- butylenebiscarboxamide (14.8g., M.P. 193.4196.2 C.).

Reduction of N,N'-bis[2-(m-nitrophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide with diborane aflfords N,N'- (1,6 hexylene)bis[2 m-nitrophenyl)-2-hydroxyethy1- amine] (II: Ar=m-'O;;NC H X= (CHEXAMPLE 18 In a manner similar to that of Example 1, condensation ofa-amine-p-nitroacetophenone hydrochloride (three runs, g., 13 g. and g.)and adipoyl chloride (2.11 g., 5.5 g. and 6.33 g.) and tworecrystallizations of the combined products (21 g.) fromN,N-dimethylformamide gave N,N'-bis[2(p-nitrophenyl)-2-oxoethyl]1,4-buty1- enebiscarboxamide (10.0 g., M.P.218.6-222.0 C.).

In a manner similar to that of Example 1, reduction of N,N'-bis[2(p-nitrophenyl)-2-oxoethyl]-1,4-butylenebiscarboxamide (48 g.) withdiborane (1 M in tetrahydrofuran, 815 ml.) and recrystallization of theresulting product (40 g.) from methanol gave N,N'-(1,6-hexylene)-bis[2(p-nitrophenyl)-2-hydroxyethylamine] (II: Ar=p-O NC -H X-= (CH (21.2 g.,M.P. 124- EXAMPLE 19 Condensation ofu-amino-p-(methylsulfonyl)acetophenone hydrochloride and adipoylchloride affords N,N'- bis[2 (p-(methylsulfonyl)phenyl) 2 oxoethyl]-1,4-butylenebiscarboxamide Reduction ofN,N'-bis[2-(p-(methylsulfonyl)phenyl)- 10 2-oxoethyl] 1,4butylenebiscarboxamide with lithium aluminum hydride affordsN,N'-(1,6-hexylene)-bis[2-(p- (methylsufonyl) phenyl) 2hydroxyethylamine] (H: "=P' a 2 6 4 2) 4) EXAMPLE 21 In a manner similarto that of Example 1, condensation of a-amino-3,4-dichloroacetophenonehydrochloride (20 g.) and succinyl chloride (6.35 g.) andrecrystallization of the resulting product 13.6 g.) fromN,N-dimethylformamide gave N,N'-bis[2-(3,4-dichlorophenyl)-2-oxoethyl]ethylenebiscarboxamide (I: Ar=3,4-Cl C H X=(CH Y+Y' =0) (10.2g., M.P. 202.6 205.0 C.).

Reduction ofN,N-bis[2-(3,4-dichlorophenyl)-2-oxoethyl]ethylenebiscarboxamide withlithium aluminum hydride afiords N,N'(1,4-butylene)-bis[2-(3,4-dichlorophenyl) 2 hydroxyethylamine] (II:Ar-=3,4-Cl C H EXAMPLE 22 In a manner similar to that of Example 1,condensation of a-amino-p-nitroacetophenone hpdrochloride (four runs, 15g. twice and 20 g. twice) and succinyl chloride (5.35 g. twice and 7.15g. twice) and four recrystallizations of the combined products fromN,N-dimethylformamide gaveN,N'-bis[2-(p-nitrophenyl)-2-oxoethyl]ethylenebiscarboxamide (I: Ar=p-ONC H X= (CH Y+Y'=O) (12.4 g., M.P. 224.0" C. with decomposition).

Reduction of N,N'-bis[2-(p-nitrophenyl)-2-oXoethyl]-ethylenebiscarboxamide with lithium aluminum hydride alfords N,N'-1,4-butylene -bis [2- (p-nitrophenyl -2-hydroxyethylamine] (II: Ar=p-ONC H X=(CH EXAMPLE 23 Condensation of a-amino-p-bromoacetophenonehydrochloride and glutaryl chloride affordsN,N-bis[2-(pbromophenyl)-2-oxoethy1]-1,3 propylenebiscar-boxamidc (I:Ar=p-BrC H X= (CH Y+Y =0).

Reduction of N,N'-bis[2(pbromophenyl)-2-oxoethyl]-1,3-propylenebiscarboxamide with lithiumaluminum hydride a'ifords N,N'-(1,5 pentylene)-bis[2-(p-br0mophenyl) 2hydroxyethylamine] (II: Ar =p-BrC H EXAMPLE 24 Condensation ofa-amino-p-bromoacetophenone hydrochloride and pimeloyl chloride afiordsN,N-bis[2-(pbromophenyl)-2Foxoethy1]1,5 pentylenebiscarboxamide (I:AI=P-BI'C6H4, X=(OH2)5, Y+Y'=0).

Reduction of N,N'-bis [2- (p-bromophenyl)-2-oxoethyl]-1,5-pentylenebiscarboxamide with lithium aluminum hydride affordsN,N'-(1,7-heptylene)-bis[2-(p-bromopheny1)-2-hydroxyethylamine] (II:Ar=p-BrC -H EXAMPLE 25 Condensation of a-amino-p-bromoacetophenonehydrochloride and suberoyl chloride affordsN,N'-bis[2-(pbromophenyl)-Z-oxoethyl] 1,6 hexylcnebiscarboxamide (I:AP=P-BI'C6H4, X: (CI-L93,

Reduction of N,N'-bis [2- (p-bromophenyl)-2-oxoethyl]-'1,6-hexylenebiscarboxamide with lithium aluminum hydride aifordsN,N'-(1,8-octylene)-bis[2-(p-bromophenyl)- 2-hydroxyethylamine] (II:Ar=p-BrC H X= (CHQ EXAMPLE 26 Condensation ofa-aminofi-bromoacetophenone hydrochloride and azelaoyl chloride affordsN,N'-bis[2(pbromophenyl) 2 oxoethyl] 1,7 heptylenebiscarbox amide (I: Ar=p-BrC H X= (OH Y+Y'=0).

Reduction of N,N'-bis [2- (p-bromophenyl)-2-oxoethyl]-1,7-heptylenebiscarboxamide with lithium aluminum hydride affordsN,N'-(l,9-nony1ene)-bis [2-(p-bromophenyl)-2-hydroxyethylamine] (II:Ar=p-BrC H 1 1 EXAMPLE 27 Condensation of a-amino-p-bromoacetophenonehydrochloride and sebaco'yl chloride affords N,N-bis[2-(pbromophenyl)-Z-oxoethyl] 1,8 octylenebiscarboxamide (IIAI'=P-BI'CGH4, X=(CH2)8,

Reduction of N,N'-bis 2- (p-bromophenyl -2-oxoethyl]1,8-octylenebiscarboxamide with lithium aluminum hydride affordsN,N'-(1,10-decylene)-bis[2-(p-bromophenyl)-2-hydroxyethylamine] II: Ar=p-BrC H EXAMPLE 28 Condensation of a-amino-p-bromoacetophenonehydrochloride and 1,9-nonylenebiscarbonyl chloride aifordsN,N-bis[2-(p-bromophenyl) 2 oxoethyl]-l,9'-nonylenebiscarboxamide (I:Ar=p-BrC H X=(CH Reduction of N,N-bis [2-(p-bromopheny1)-2-oxoethyl]-1,9-nonylenebiscarboxamide with lithium aluminum hydride affords N,N'(1,11 undec'ylene)-bis[2-(p-bromophenyl) 2 hydroxycthylaminc] (II:Ar=p-'BrC H 2)9)- EXAMPLE 29 Condensation of u-amino-p-bromoacetophenonehydrochloride and 1,10-decylenebiscarbonyl chloride afiordsN,N'-bis[2-(p-bromophenyl) 2 oxoethyl]-1,10-decylenebiscarboxamide (I:Ar=p-BrC H X= (CH Y+Y'=0).

Reduction of N,N'-bis [2-(p-bromopheny1) -2-oxoethyl]1,10-decylenebiscarboxamide with lithium aluminum hydride affords N,N'(1,12 dodecylene)-bis[2- (p-bromophenyl) 2 hydroxyethylamine] (II:Ar=p-BrC H X= 2)1o)- EXAMPLE 30 Condensation ofa-amino-p-bromoacetophenone hydrochloride and 3-methyladipo'yl chlorideaffords N,N'-bis[2- (pbromophenyl 2 oxoethyl] 2methyl-1,4-buty1enebiscarboxamide (I: Ar=pBrC H Reduction ofN,N'-bis[2-(p-bromophenyl) -2-oxoethyl]Z-methyl-1,4-butylenebiscarboxamide with lithium aluminum hydrideaffords N,N'-(3-methyl-1,6-hexylene)-bis[2- p-b romophenyl)-2-hydroxyethyl amine] (l1: Ar=p-BrC H X=CH CH(CH )CH CH EXAMPLE 31TABLE IV Concentration (p.p.m.)

Bacterio- Bacteri- 1\licroorgauism static cidal Staphylococcus aureus100 100 Eberihella. typhi 100 100 Clostridiu'm. welchii 100 Pseudomonasaeruginosa 75 100 12 EXAMPLE 32 In a manner similar to that of Example31, reduction of N,N' bis[2(m-chlorophenyl)-2-ox0ethyl]-1,4-butylenebiscarboxamide (10 g.) withsodium borohydride (1.6 g.) and recrystallization of the resultingproduct from ethyl acetate gaveN,N-bis[2-(m-chlorophenyl)-2-hydroxyethyl1-1,4-butylenebiscarboxamideX=(CH Y=H, Y'=OH) (8.6 g., M.P. 122.6- 137.0 C.).

EXAMPLE 33 In a manner similar to that of Example 31, reduction ofN,N'-bis[2- (p-chlorophenyl) -2-oxoethyl]-1,4-buty1enebiscarboxamide(two runs, 10 g. and 27.8 g.) with sodium borohydride (1.64 g. and 4.6g.) and two recrystallizations of the combined products from methanolgave N,N'- bis[2 (p chlorophenyl) 2 hydroxyethyl] 1,4butylenebiscarboxamide (Ar=p-ClC H X= (CH =H, Y'=OH) (11.4 g., M.P.191.0193.0 C.).

EXAMPLE 34 In a manner similar to that of Example 31, reduction ofN,N-bis[2-(3,4dichloropheny1)-2-oxoethyl]-1,4-butylenebiscarboxamide (20g.) with sodium borohydride (3 g.) and recrystallization of theresulting product from ethyl acetate gaveN,N-bis[2(3,4-dichlorophenyl)-2-hydroxyethyl]-l,4-butylenebiscarboxamide(I: Ar: 3,4-C12C H3,

X=(CH Y=H, Y'=OH) (14.4 g., M.P. 133.8- 136.0 C.).

EXAMPLE 35 EXAMPLE 36 In a manner similar to that of Example 31,reduction ofN,N'-bis[2(3,4-dichloropheny1)-2-oxoethyl]ethy1enebiscarboxamide (19.5g.) with sodium borohydride (3.1 g.) and trituration of the resultingproduct with methanol gave N,N-bis[2-(3,4-dichlorophenyl)-2-hydroxcthyl]ethylenebiscarboxamide (I: Ar=3,4-Cl C H X=(CH Y=H, Y'=OH) (9 g., M.P.209.2212-6 C.).

I claim:

1. N,N' bis[2 (Ar) 2 (Y) 2 (Y') ethyl] (X)- bis-carboxamide of theformula Ar is phenyl substituted by one to three members selected fromthe group consisting of non-tertiary, a tertiary alkoxy of one to fourcarbon atoms and halo or by a member selected from the group consistingof trifiuoromethyl, dimethylamino, acetamido, nitro, methylthio andmethylsulfonyl;

X is alkylene of two to ten carbon atoms with bonds to the adjacentcarbon atoms at different carbon atoms; and

Y taken together with Y is carbonyl oxygen.

2. N,N' bis[2 (p bromophenyl) 2 oxoethyl] 1,4 butylenebiscarboxamideaccording to claim 1.

3. N,N' bis[2 (p methoxyphenyl) 2 oxoethyl1- 1,4-butylenebiscarboxamideaccording to claim 1.

4. N,N bis[2 (m chlorophenyl) 2 oxoethyl]- 1,4-butylenebiscarboxamideaccording to claim 1.

5. N,N' bis[2 (p chlorophenyl) 2 oxoethyl] 1,4- u ylenebiscarboxamideaccording to claim 1.

6. N,N' bis[2 (3,4 dichlorophenyl) 2 oxoethyl]-1,4-butylenebiscarboxamide according to claim 1.

7. N,N' -bis[2 (2,5 dichlorophenyl) 2 oxoethyl]-1,4-buty1enebiscarboxamide according to claim 1.

8. N,N' bis[2 (m nitrophenyl) 2 oxoethyl] 1,4- butylenebiscarboxamideaccording to claim 1.

9. N,N' bis [2-(p nitrophenyl) 2 oxoethyl] 1,4- butylenebiscarboxamideaccording to claim 1.

10. N,N' bis[2 (p methylthiophenyl) 2oxoethyl]1,4-butylenebiscarboxamide according to claim 1.

11. N,N' bis[2 (3,4 dichlorophenyl) 2 oxoethyl]-ethylenebiscarboxamideaccording to claim 1.

12. N,N' bis[2 (p nitrophenyl) 2 oxoethyl]- ethylenebiscarboxamideaccording to claim 1.

13. N,N'-bis[2 (Ar) 2 (Y) 2 (Y) ethyl]- (X)-biscarboxamide of theformula wherein:

Ar is phenyl or phenyl substituted by one to three members selected fromthe group consisting of non-tertiary alkyl of one to four carbon atoms,non-tertiary alkoxy of one to four carbon atoms and halo or by a memberselected from the group consisting of trifiuoromethyl, dimethylamino,acetamido, nitro, methylthio and methylsulfonyl;

X is alkylene of two to ten carbon atoms with bonds to the adjacentcarbon atoms at different carbon atoms;

Y is hydrogen; and

Y is hydroxyl.

14. N,N' bis[2 (p bromophenyl) 2hydroxyethyl]-1,4-butylenebiscarboxamide according to claim 13.

15. N,N' bis[2 (m -chlorophenyl) 2hydroxyethyl]-1,4-butylenebiscarboxamide according to claim 13.

16. N,N' bis[2 (p chlorophenyl) 2hydroxyethyl]-1,4-butylenebiscarboxamide according to claim 13.

17. N,N' bis[2 (3,4 dichlorophenyl) 2hydroxyethy1]-1,4-butylenebiscarboxamide according to claim 13.

18. N,N' bis[2 (p methylthiophenyl) 2hydroxyethyl]-1,4-butylenebiscarboxamide according to claim 13.

19. N,N' bis[2 (3,4 dichlorophenyl) 2hydroxyethyl]-ethylenebiscarboxamide according to claim 13.

References Cited UNITED STATES PATENTS 3,148,216 9/1964 Shapiro et a1.260558 3,148,194 9/1964 Waugh et al 260307 2,483,392 10/1949 Meyer eta1. 26'0-307 OTHER REFERENCES Nagornaya et al., Chem. Abst., vol. 59,col. 3998a-b (1963).

Sych et al., Chem. Abstract, vol. 63, col. 4424b-e (1965).

Sych et a1. 11, Optics & Spectroscopy, vol. 13, p. 288- (1962).

HARRY I. MOATZ, Primary Examiner U.S. Cl. X.R.

260562 R, 570.5 C, 559 A; 424-324 UNITED STATES PATENT AND TRADEMARKOFFICE CERTIFICATE OF CORRECTION PATENTNO.: 3,775, t77

DATED November 27, 973

INVENTOR(S) Guy D. Diana It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Claim 1, line 6, a tertiary" should be deleted.

Signed and Scaled this Ninth D3) Of November 1976 [SEAL] I t A ttesr:

RUTH C. MASON (mrrmr'ssr'unvr nf Pan'nrs and Trademarks

